Insufficient sleep is a major health and safety problem for Americans. National polls indicate that more than a quarter of adults 18-84 years of age regularly sleep less than 7 h per night, with 15% reporting sleeping less than 6 h per night. The deficits in alertness and performance ability associated with insufficient sleep can lead to greater risk for automobile accidents, home and workplace accidents, and on-the-job errors in sleepy individuals. Insufficient sleep can also have a negative effect on the quality of life, with impacts on irritability, mood, and motivation. Despite recognition of inter-individual differences in the timing of peak performance and in the response to acute sleep deprivation, very little is known regarding inter-individual differences in response to both chronic and acute sleep deprivation. A series of recent findings have revealed that genetic polymorphisms account for considerable inter-individual variations in the response to acute sleep loss/circadian misalignment and in sensitivity to the most commonly used wake-promoting therapeutic, caffeine. These studies, however, have not examined the inter-individual differences in response to chronic sleep restriction, nor have they examined the inter-individual differences in circadian and homeostatic contributions to alertness and cognitive performance. Two major determinants of objective performance, subjective alertness and sleep are circadian phase and sleep-wake homeostasis. Recently, a genetic polymorphism in the circadian clock gene PER3 has been linked to inter-individual differences in sleep, wake-time performance and response to sleep deprivation, with PER3*1* individuals sleeping and performing better during prolonged wake episodes while PER3515 individuals sleep and perform better after circadian phase advances. Therefore, the goal of the proposed work is to evaluate the phenotype of individuals with polymorphisms in the PER3 gene that are known to affect sleep homeostasis and circadian rhythms in performance. We propose to study 6 healthy individuals with the PEf?3"M genotype and 6 with the PER3515 genotype. The protocol will include a 23-day inpatient stay with 2 weeks of chronic sleep restriction in a forced desynchrony procedure, which will enable us to investigate both the circadian and wake-dependent contributions to alertness and performance, followed by one 40-hr sleep deprivation, which will enable us to investigate the response to an episode of acute sleep deprivation following chronic sleep restriction. We will record sleep and waking EEC, and test for multiple aspects of cognitive functioning, alertness and mood. PUBLIC RELEVANCE: Results from this study have important implications for understanding the consequences of chronic and acute insufficient sleep. Most adults regularly fail to get sufficient sleep, but few studies have attempted to quantify the inter-individual differences in response to this adverse situation. Knowledge of how the alertness and performance of PER34'4 and PER3515 individuals respond to insufficient sleep will provide needed information about the interaction of sleep, circadian biology, neurobehavioral performance and genetics.